Professor (Dr. )Namrata Chhabra
27-Jan-18 1Biochemistry for medics- Lecture Notes- Namrata Chhabra
1) Chemistry, and metabolism of vitamin K
2) Biological significance,
3) Vitamin K deficiency -Causes, and clinical implications
4) Mechanism of action of vitamin K antagonists
27-Jan-18 Biochemistry for medics- Lecture Notes- Namrata Chhabra 2
Vitamin K represents a group of lipophilic and hydrophobic
Originally identified for its role in the process of blood clot
("K" is derived from the German word "koagulation")
27-Jan-18 Biochemistry for medics- Lecture Notes- Namrata Chhabra 3
Three compounds have the biological activity of vitamin K
Phylloquinone (Vitamin K1), the normal dietary source, found in green
Menaquinones (vitamin K2), synthesized by intestinal bacteria, with
differing lengths of side chain;
and Menadione and menadiol diacetate, synthetic compounds that can
be metabolized to phylloquinone.
27-Jan-18 4Biochemistry for medics- Lecture Notes- Namrata Chhabra
Phylloquinone have a 20 C side
Menaquinones have a 30 C side
The synthetic vitamin K
(menadione, menadiol diacetate)
have only hydrogen in place of
isoprenoid side chain that makes
these vitamin water-soluble.
Isoprenoid side chain
Green leafy vegetables such as kale and spinach,
Margarine and liver.
Vegetable oils and particularly olive, canola, and soybean oils.
Some amount is contributed by intestinal bacteria
27-Jan-18 6Biochemistry for medics- Lecture Notes- Namrata Chhabra
Absorption, Transportation and
Absorption takes place in small intestine
in the presence of bile salts.
The transportation from intestine is
carried out through chylomicrons.
Storage occurs in liver and from liver
transportation to peripheral cells is
carried out bound with beta lipoproteins
27-Jan-18 7Biochemistry for medics- Lecture Notes- Namrata Chhabra
Conditions causing impaired absorption of
is associated with
vitamin K and
other fat soluble
27-Jan-18 8Biochemistry for medics- Lecture Notes- Namrata Chhabra
Impaired absorption of vitamin K
27-Jan-18 Biochemistry for medics- Lecture Notes- Namrata Chhabra 9
vitamin K may also
be decreased by
mineral oil, bile
Recommended daily allowance
The average daily allowance is 50-120
Requirement increases in –
Patients on prolonged antibiotic therapy,
bile acid sequestrants (Cholestyramine,
colestipol) and Orlistat (weight loss
27-Jan-18 10Biochemistry for medics- Lecture Notes- Namrata Chhabra
Functions of Vitamin K
27-Jan-18 Biochemistry for medics- Lecture Notes- Namrata Chhabra 11
Mechanism of action of vitamin K
Vitamin K has an important role in post-
translational modification of calcium binding
Vitamin K-dependent gamma-carboxylation occurs
only on specific glutamic acid residues in a small
number of vitamin K-dependent proteins, it is critical
to the calcium-binding function of those proteins.
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Vitamin K-dependent gamma-carboxylation
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Vitamin K acts as a
cofactor for Carboxylase
enzyme that catalyzes
glutamic acid, resulting
in its conversion to
glutamic acid (Gla).
1) Role of vitamin K in coagulation
Factors II (prothrombin), VII, IX, and X make up the core of the
These factors are synthesized in the liver in the inactive form.
They undergo post translational modifications, gamma carboxylation of
glutamic acid residues.
27-Jan-18 14Biochemistry for medics- Lecture Notes- Namrata Chhabra
Role of vitamin K in coagulation
Gamma carboxylation imparts another negative charge to promote the
effective binding of these factors/proteins to calcium ions.
γ-Carboxyglutamates by chelating calcium ions, therefore, permit the
binding of the blood clotting proteins to membranes.
Prothrombin and several other proteins of the blood clotting system
(Factors VII, IX, and X, and proteins C and S) each contain 4–6 γ-
27-Jan-18 15Biochemistry for medics- Lecture Notes- Namrata Chhabra
Vitamin K cycle
Vitamin K is a fat-soluble vitamin, the body stores very little of it, and its
stores are rapidly depleted without regular dietary intake.
Because of its limited ability to store vitamin K, the body recycles it
through a process called the vitamin K cycle.
The vitamin K cycle allows a small amount of vitamin K to function in the
gamma-carboxylation of proteins many times, decreasing the dietary
27-Jan-18 17Biochemistry for medics- Lecture Notes- Namrata Chhabra
Vitamin K cycle
Reduced lipoamide is required for the activity of
Epoxide reductase and NADPH is needed for the
action of vitamin K reductase.
27-Jan-18 18Biochemistry for medics- Lecture Notes- Namrata Chhabra
Vitamin K Antagonists
Dicumarol and Warfarin, inhibit coagulation through antagonism
of the action of vitamin K.
These are competitive inhibitor of Epoxide reductase.
By preventing recycling of vitamin K inhibiting two important
reactions , these drugs create a functional vitamin K deficiency
In the presence of Warfarin, vitamin K epoxides cannot be reduced,
they accumulate and are excreted.
27-Jan-18 19Biochemistry for medics- Lecture Notes- Namrata Chhabra
Role of vitamin K in blood coagulation
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Indications for using vitamin K antagonists
The main indications for a patient to receive vitamin K antagonists (VKAs)
are the following:
Mechanical Heart Valves
Deep Vein Thrombosis and Pulmonary Embolism
Acute Ischemic Stroke
The pathological formation of a blood clot, or thrombosis, poses significant
health risks in such patients
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Some facts about Vitamin K Antagonists
Large quantities of dietary or supplemental vitamin K can overcome the
anticoagulant effect of vitamin K antagonists
The major side effect of Warfarin is bleeding. INR (international
normalized ratio-a laboratory measurement of how long it takes
blood to form a clot) is used to determine the effects of oral
anticoagulants on the clotting system.
In healthy people an INR of 1.1 or below is considered normal. An INR
range of 2.0 to 3.0 is generally an effective therapeutic range for people
27-Jan-18 22Biochemistry for medics- Lecture Notes- Namrata Chhabra
2) Synthesis of Bone
Vitamin K is also important in synthesis of two proteins that contain γ-
carboxyglutamate that are present in bone- osteocalcin and bone matrix
Osteocalcin is a protein synthesized by osteoblasts.
The synthesis of osteocalcin by osteoblasts is regulated by the active
form of vitamin D, 1,25(OH)2D3 or calcitriol.
The mineral-binding capacity of osteocalcin requires vitamin K-
dependent gamma-carboxylation of three glutamic acid residues.
27-Jan-18 23Biochemistry for medics- Lecture Notes- Namrata Chhabra
Synthesis of Bone Calcium-Binding Proteins
After gamma carboxylation
osteocalcein binds tightly to
27-Jan-18 24Biochemistry for medics- Lecture Notes- Namrata Chhabra
Treatment of pregnant women with Warfarin can lead
to fetal bone abnormalities (Fetal Warfarin syndrome)
Synthesis of Bone Calcium-Binding Proteins
Matrix Gla protein- MGP has been found in bone, cartilage, and soft
tissue, including blood vessels. MGP prevents the calcification of soft
tissues and cartilages, while facilitating normal bone growth and
Protein S- The vitamin K-dependent anticoagulant protein S is also
synthesized by osteoblasts, but its role in bone metabolism is unclear.
Children with inherited protein S deficiency suffer complications related
to increased blood clotting as well as decreased bone density.
27-Jan-18 25Biochemistry for medics- Lecture Notes- Namrata Chhabra
Vitamin K deficiency
27-Jan-18 26Biochemistry for medics- Lecture Notes- Namrata Chhabra
Vitamin K deficiency in the newborn
27-Jan-18 27Biochemistry for medics- Lecture Notes- Namrata Chhabra
The main symptom is bleeding (hemorrhage)—into the skin (causing
bruises), from the nose, from a wound, in the stomach, or in the intestine.
Blood may be seen in the urine or stool.
In newborns, life-threatening bleeding within or around the brain may
27-Jan-18 28Biochemistry for medics- Lecture Notes- Namrata Chhabra
Hallmarks of vitamin K deficiency
27-Jan-18 29Biochemistry for medics- Lecture Notes- Namrata Chhabra
A Prothrombin time (PT)
Activated partial Thromboplastin time (aPTT),
Fibrinogen levels, and
A platelet count can be included in the initial workup for
vitamin K deficiency bleeding (VKDB) in a newborn.
Full coagulation profile
27-Jan-18 30Biochemistry for medics- Lecture Notes- Namrata Chhabra
A prolonged PT is usually the
first laboratory test result to be
abnormal in vitamin K
deficiency bleeding due to
reduction in Prothrombin, FVII,
FIX, and FX levels.
27-Jan-18 31Biochemistry for medics- Lecture Notes- Namrata Chhabra
Patients with liver disease may have an elevated prothrombin
time because of liver cell destruction as well as vitamin K
If an elevated prothrombin time does not improve on vitamin K
therapy, it can be deduced that it is not the result of vitamin K
27-Jan-18 32Biochemistry for medics- Lecture Notes- Namrata Chhabra
Treatment of vitamin K deficiency
For patients with chronic
malabsorption, 1–2 mg/d of vitamin K
should be given orally,
or 1–2 mg/week can be taken
27-Jan-18 33Biochemistry for medics- Lecture Notes- Namrata Chhabra
A vitamin K injection in the muscle is
recommended for all newborns to
reduce the risk of bleeding within the
brain after delivery.
27-Jan-18 34Biochemistry for medics- Lecture Notes- Namrata Chhabra
Toxicity from dietary phylloquinone and menaquinones has not
High doses of vitamin K can impair the actions of oral
27-Jan-18 35Biochemistry for medics- Lecture Notes- Namrata Chhabra
Vitamin K is a fat soluble vitamin
Phylloquinone, Menaquinone and Menadione are the members of vitamin K
Vitamin K acts as a coenzyme for the gamma carboxylation of glutamic residues
of Calcium binding proteins
Plays an important role in blood clotting, bone formation and prevention of
calcification of soft tissues
Deficiency of vitamin K is manifested in the form of bleeding tendencies and
Oral or injectable vitamin K can be recommended depending upon the severity
of the disease.
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